Integrins are heterodimeric transmembrane proteins located on the surface of cells, which play an important part in the adhesion of cells to an extracellular matrix. They recognize extracellular glycoproteins such as fibronectin or vitronectin on the extracellular matrix by means of the RGD sequence occurring in these proteins (RGD is the single-letter code for the amino acid sequence arginine-glycine-aspartate).
In general, integrins such as, for example, the vitronectin receptor, which is also referred to as the .alpha..sub.v.beta..sub.3 receptor, or alternatively the .alpha..sub.v.beta., receptor or the GpIlb/lIIa receptor, play an important part in biological processes such as cell migration and cell-matrix adhesion and thus in diseases in which these processes are crucial steps. Examples which may be mentioned are cancer, osteoporosis, arteriosclerosis, restenosis (fresh occurrence of a stenosis after a surgical intervention as a result of damage to the vascular wall) and ophthalmia (a certain type of inflammation of the eye).
The .alpha..sub.v.beta..sub.3 receptor occurs, for example, in large amounts on growing endothelial cells and makes possible their adhesion to an extracellular matrix. Thus the .alpha..sub.v.beta..sub.3 receptor plays an important part in angiogenesis, i.e. the formation of new blood vessels, which is a crucial requirement for tumor growth and metastasis formation in carcinomatous disorders. Furthermore, it is also responsible for the interaction between osteoclasts, i.e. cells resorbing mineralized tissue, and the bone structure. The first step in the degradation of bone tissue consists in adhesion of osteoclasts to the bone. This cell-matrix interaction takes place via the .alpha..sub.v.beta..sub.3 receptor, which is why the corresponding integrin plays an important part in this process. Osteolytic diseases such as osteoporosis are caused by an inequilibrium between bone formation and bone degradation, i.e. the resorption of bone material caused by addition of osteoclasts predominates.
It was possible to show that the blocking of the abovementioned receptors is an important starting point for the treatment of disorders of this type. If the adhesion of growing endothelial cells to an extracellular matrix is suppressed by blocking their corresponding integrin receptors, for example by a cyclic peptide or a monoclonal antibody, the endothelial cells die. Angiogenesis therefore does not occur, which leads to a stoppage or regression of tumour growth (cf., for example, Brooks et al., Cell, Volume 79, 1157-1164, 1994).
Moreover, the invasive properties of tumour cells and thus their ability for metastasis formation are markedly decreased if their .alpha..sub.v.beta..sub.3 receptor is blocked by an antibody (Brooks et al., J. Clin. Invest., Volume 96, 1815, 1995).
The degradation of bone tissue can obviously be suppressed by blockage of the .alpha..sub.v.beta..sub.3 receptors of the osteoclasts, since these are then unable to accumulate on the bone in order to resorb its substance (WO 98/18461, p. 1, 1.24 to p.2,1. 13).
As a result of the blockage of the .alpha..sub.v.beta..sub.3 receptor on cells of the aorta smooth vascular musculature with the aid of integrin receptor antagonists, it is possible to suppress the migration of these cells into the neointima and thus angioplasty leading to arteriosclerosis and restenosis (Brown et al., Cardiovascular Res., Volume 28, 1815, 1994).
In recent years, compounds have therefore been sought which act as antagonists of integrin receptors. For example, WO98/00395 discloses the para-substituted phenylalanine derivative (I), which exhibits an IC.sub.50 value of 0.13 nM in an .alpha..sub.v.beta..sub.3 receptor assay and an IC.sub.50 value of 0.16 nM in an .alpha..sub.v.beta..sub.5 receptor assay: ##STR2##
.omega.-Phenylcarboxylic acids having a phenyl residue which is linked to the phenyl group via a linker group and having a guanidine unit or a guanidine mimic are disclosed, for example in WO 97/36858, WO 97/36859, WO 97/36860 and WO 97/36862. According to these laid-open patent applications, the linker group can be an amide, sulphonamide, ester, urea, ether, thioether, sulphoxide, sulphone or ketone unit which may be extended by an additional methylene group, or can be a saturated or unsaturated alkylene bridge.
In particular, WO 97/36859, in addition to numerous substances comprised by a general formula, actually discloses 3-phenylpropionic acid derivatives such as (II) or (III). While the .alpha.-phenylalanine derivative (II) exhibits an IC.sub.50 value of 0.18 nM with respect to its activity as an .alpha..sub.v.beta..sub.3 antagonist in in-vitro investigations, the succinic acid derivatives (III) have IC.sub.50 values in the range from 38.7 to 141 nM in the same investigations: ##STR3## EQU R=OH, OEt, NHCH.sub.2 COOH
WO 97/36862, in addition to numerous substances comprised by a general formula, actually describes .beta.-substituted propionic acid derivatives such as (IV) or (V). The sulphonamide-bridged derivative (IV) exhibits an lC.sub.50 value of 16.7 nM with respect to its activity as an .alpha..sub.v.beta..sub.3 antagonist in in-vitro investigations, while the amide-bridged derivatives (V) have IC.sub.50 values in the range from 0.87 to 11.6 nM in the same investigations: ##STR4##
R=methyl, isopropyl, phenyl, 3,5-difluorophenyl ##STR5##
None of the abovementioned laid-open patent applications, however, discloses .beta.-phenylalanine derivatives or their activity as .alpha..sub.v.beta..sub.3 antagonists.
.beta.-Phenylalanine derivatives as .alpha..sub.v.beta..sub.3 antagonists are disclosed, for example, in U.S. Pat. No. 5,639,765, WO 97/08145 and WO 97/36861, the linkage of the carboxyl residue to the central group consisting of two phenyl units bonded to one another via a linker group being carried out in these compounds, if a central group of this type is present at all, via the amino group. For example, the compound (VI) disclosed in WO 97/36861 exhibits an IC.sub.50 value of 1.66 nM with respect to its activity as an .alpha..sub.v.beta..sub.3 antagonist in in-vitro investigations. ##STR6##
It was the object of the present invention to develop compounds which exhibit a high activity as integrin antagonists and in particular against the .alpha..sub.v.beta..sub.3 and/or the .alpha..sub.v.beta..sub.3 receptor.